Leukemia, Myelodysplasia, Transplantation

Photo by Rhoda Baer

New research suggests guidelines from the National Comprehensive Cancer Network (NCCN) may sometimes be supported by low-quality evidence or no evidence at all.

Researchers compared NCCN recommendations for cancer drugs to US cancer drug approvals over a 5-year period.

Thirty-nine percent of NCCN’s treatment recommendations did not coincide with uses approved by the US Food and Drug Administration (FDA).

For most of these recommendations (84%), NCCN did not provide supporting data from randomized, phase 3 trials.

For 36% of the recommendations, NCCN gave no supporting evidence.

Vinay Prasad, MD, of Oregon Health & Science University in Portland, Oregon, and his colleagues reported these findings in The BMJ.

Dr Prasad and his colleagues compared FDA approvals of cancer drugs between 2011 and 2015 with NCCN recommendations as of March 25, 2016.

When NCCN made recommendations beyond FDA approvals, the researchers evaluated the evidence used to support those recommendations.

Forty-seven new cancer drugs were approved by the FDA for 69 indications between 2011 and 2015. NCCN recommended the 47 drugs for 113 indications, including the 69 FDA-approved indications.

So 39% (n=44) of NCCN’s recommendations were not approved by the FDA, and NCCN gave the following evidence to support these recommendations:

• No evidence—36% (n=16)
• Phase 2 trial without randomization—30% (n=13)
• Randomized, phase 3 trial—16% (n=7)
• Phase 2 trial with randomization—7% (n=3)
• Case report or series of less than 5 patients—5% (n=2)
• Book chapter or review article—2% (n=1)
• Phase 1 trial—2% (n=1)
• Ongoing trial—2% (n=1).

Dr Prasad and his colleagues did point out that not all FDA approvals are supported by randomized, phase 3 trials.

And when the team followed-up 21 months after their initial analysis, they found that 6 of the 44 (14%) additional recommendations by NCCN had received FDA approval.

The researchers also noted that they did not search for independent evidence to support NCCN recommendations beyond the references NCCN provided. So some of the recommendations may have had more or better supporting evidence than what was provided.

Still, the team said these results suggest NCCN “frequently” makes recommendations that go beyond FDA approvals and “often fails to cite evidence or relies on low levels of evidence.” Therefore, NCCN should cite all evidence used to formulate its recommendations.

NCCN argues that it does provide ample evidence to support the recommendations in its guidelines.

“The NCCN guidelines contain more than 24,500 references to inform users of the evidence used in making its decisions,” said Robert W. Carlson, MD, chief executive officer of NCCN.

“These data are supplemented by the analysis of the available evidence by expert clinician researchers and patient advocates who evaluate each recommendation and come to consensus. Each recommendation is labeled with a Category of Evidence, and the vast majority of those for systemic therapies are accompanied by Evidence Blocks, which outline, on 1-5 scales, the efficacy, safety, quality of the evidence, consistency of the evidence, and affordability of the treatment.”

Photo by Rhoda Baer

New research suggests guidelines from the National Comprehensive Cancer Network (NCCN) may sometimes be supported by low-quality evidence or no evidence at all.

Researchers compared NCCN recommendations for cancer drugs to US cancer drug approvals over a 5-year period.

Thirty-nine percent of NCCN’s treatment recommendations did not coincide with uses approved by the US Food and Drug Administration (FDA).

For most of these recommendations (84%), NCCN did not provide supporting data from randomized, phase 3 trials.

For 36% of the recommendations, NCCN gave no supporting evidence.

Vinay Prasad, MD, of Oregon Health & Science University in Portland, Oregon, and his colleagues reported these findings in The BMJ.

Dr Prasad and his colleagues compared FDA approvals of cancer drugs between 2011 and 2015 with NCCN recommendations as of March 25, 2016.

When NCCN made recommendations beyond FDA approvals, the researchers evaluated the evidence used to support those recommendations.

Forty-seven new cancer drugs were approved by the FDA for 69 indications between 2011 and 2015. NCCN recommended the 47 drugs for 113 indications, including the 69 FDA-approved indications.

So 39% (n=44) of NCCN’s recommendations were not approved by the FDA, and NCCN gave the following evidence to support these recommendations:

• No evidence—36% (n=16)
• Phase 2 trial without randomization—30% (n=13)
• Randomized, phase 3 trial—16% (n=7)
• Phase 2 trial with randomization—7% (n=3)
• Case report or series of less than 5 patients—5% (n=2)
• Book chapter or review article—2% (n=1)
• Phase 1 trial—2% (n=1)
• Ongoing trial—2% (n=1).

Dr Prasad and his colleagues did point out that not all FDA approvals are supported by randomized, phase 3 trials.

And when the team followed-up 21 months after their initial analysis, they found that 6 of the 44 (14%) additional recommendations by NCCN had received FDA approval.

The researchers also noted that they did not search for independent evidence to support NCCN recommendations beyond the references NCCN provided. So some of the recommendations may have had more or better supporting evidence than what was provided.

Still, the team said these results suggest NCCN “frequently” makes recommendations that go beyond FDA approvals and “often fails to cite evidence or relies on low levels of evidence.” Therefore, NCCN should cite all evidence used to formulate its recommendations.

NCCN argues that it does provide ample evidence to support the recommendations in its guidelines.

“The NCCN guidelines contain more than 24,500 references to inform users of the evidence used in making its decisions,” said Robert W. Carlson, MD, chief executive officer of NCCN.

“These data are supplemented by the analysis of the available evidence by expert clinician researchers and patient advocates who evaluate each recommendation and come to consensus. Each recommendation is labeled with a Category of Evidence, and the vast majority of those for systemic therapies are accompanied by Evidence Blocks, which outline, on 1-5 scales, the efficacy, safety, quality of the evidence, consistency of the evidence, and affordability of the treatment.”

Photo by Rhoda Baer

New research suggests guidelines from the National Comprehensive Cancer Network (NCCN) may sometimes be supported by low-quality evidence or no evidence at all.

Researchers compared NCCN recommendations for cancer drugs to US cancer drug approvals over a 5-year period.

Thirty-nine percent of NCCN’s treatment recommendations did not coincide with uses approved by the US Food and Drug Administration (FDA).

For most of these recommendations (84%), NCCN did not provide supporting data from randomized, phase 3 trials.

For 36% of the recommendations, NCCN gave no supporting evidence.

Vinay Prasad, MD, of Oregon Health & Science University in Portland, Oregon, and his colleagues reported these findings in The BMJ.

Dr Prasad and his colleagues compared FDA approvals of cancer drugs between 2011 and 2015 with NCCN recommendations as of March 25, 2016.

When NCCN made recommendations beyond FDA approvals, the researchers evaluated the evidence used to support those recommendations.

Forty-seven new cancer drugs were approved by the FDA for 69 indications between 2011 and 2015. NCCN recommended the 47 drugs for 113 indications, including the 69 FDA-approved indications.

So 39% (n=44) of NCCN’s recommendations were not approved by the FDA, and NCCN gave the following evidence to support these recommendations:

• No evidence—36% (n=16)
• Phase 2 trial without randomization—30% (n=13)
• Randomized, phase 3 trial—16% (n=7)
• Phase 2 trial with randomization—7% (n=3)
• Case report or series of less than 5 patients—5% (n=2)
• Book chapter or review article—2% (n=1)
• Phase 1 trial—2% (n=1)
• Ongoing trial—2% (n=1).

Dr Prasad and his colleagues did point out that not all FDA approvals are supported by randomized, phase 3 trials.

And when the team followed-up 21 months after their initial analysis, they found that 6 of the 44 (14%) additional recommendations by NCCN had received FDA approval.

The researchers also noted that they did not search for independent evidence to support NCCN recommendations beyond the references NCCN provided. So some of the recommendations may have had more or better supporting evidence than what was provided.

Still, the team said these results suggest NCCN “frequently” makes recommendations that go beyond FDA approvals and “often fails to cite evidence or relies on low levels of evidence.” Therefore, NCCN should cite all evidence used to formulate its recommendations.

NCCN argues that it does provide ample evidence to support the recommendations in its guidelines.

“The NCCN guidelines contain more than 24,500 references to inform users of the evidence used in making its decisions,” said Robert W. Carlson, MD, chief executive officer of NCCN.

“These data are supplemented by the analysis of the available evidence by expert clinician researchers and patient advocates who evaluate each recommendation and come to consensus. Each recommendation is labeled with a Category of Evidence, and the vast majority of those for systemic therapies are accompanied by Evidence Blocks, which outline, on 1-5 scales, the efficacy, safety, quality of the evidence, consistency of the evidence, and affordability of the treatment.”

The tyrosine kinase inhibitor ibrutinib (Imbruvica) may be associated with early-onset invasive fungal infections (IFI) in patients with hematologic malignancies, investigators caution.

French investigators identified 33 cases of invasive fungal infections occurring among patients who had been treated with ibrutinib as monotherapy or in combination with other agents. Of the 33 cases, 27 were invasive aspergillosis, and 40% of these were localized in the central nervous system. The findings were published in the journal Blood.

“IFI tend to occur within the first months of treatment and are infrequent thereafter. Whilst it seems difficult at this point to advocate for systematic antifungal prophylaxis in all patients, an increased awareness about the potential risk of IFI after initiating ibrutinib is warranted, especially when other predisposing factors are associated,” wrote David Ghez, MD, PhD, and colleagues at the Gustave Roussy Institute in Villejuif and other centers in France.

Although ibrutinib, an inhibitor of Bruton’s tyrosine kinase, is generally considered to be less immunosuppressive than other therapies, it was associated with five cases of Pneumocystis jirovecii pneumonia in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib monotherapy in a 2016 report (Blood. 2016;128:1940-3). Of these five patients, four were treatment naive, suggesting that ibrutinib itself could increase risk for invasive opportunistic infections, Dr. Ghez and his colleagues noted.

[email protected]

SOURCE: Ghez D et al., Blood. 2018 Feb 1. doi: 10.1182/blood-2017-11-818286.

The tyrosine kinase inhibitor ibrutinib (Imbruvica) may be associated with early-onset invasive fungal infections (IFI) in patients with hematologic malignancies, investigators caution.

French investigators identified 33 cases of invasive fungal infections occurring among patients who had been treated with ibrutinib as monotherapy or in combination with other agents. Of the 33 cases, 27 were invasive aspergillosis, and 40% of these were localized in the central nervous system. The findings were published in the journal Blood.

“IFI tend to occur within the first months of treatment and are infrequent thereafter. Whilst it seems difficult at this point to advocate for systematic antifungal prophylaxis in all patients, an increased awareness about the potential risk of IFI after initiating ibrutinib is warranted, especially when other predisposing factors are associated,” wrote David Ghez, MD, PhD, and colleagues at the Gustave Roussy Institute in Villejuif and other centers in France.

Although ibrutinib, an inhibitor of Bruton’s tyrosine kinase, is generally considered to be less immunosuppressive than other therapies, it was associated with five cases of Pneumocystis jirovecii pneumonia in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib monotherapy in a 2016 report (Blood. 2016;128:1940-3). Of these five patients, four were treatment naive, suggesting that ibrutinib itself could increase risk for invasive opportunistic infections, Dr. Ghez and his colleagues noted.

[email protected]

SOURCE: Ghez D et al., Blood. 2018 Feb 1. doi: 10.1182/blood-2017-11-818286.

The tyrosine kinase inhibitor ibrutinib (Imbruvica) may be associated with early-onset invasive fungal infections (IFI) in patients with hematologic malignancies, investigators caution.

French investigators identified 33 cases of invasive fungal infections occurring among patients who had been treated with ibrutinib as monotherapy or in combination with other agents. Of the 33 cases, 27 were invasive aspergillosis, and 40% of these were localized in the central nervous system. The findings were published in the journal Blood.

“IFI tend to occur within the first months of treatment and are infrequent thereafter. Whilst it seems difficult at this point to advocate for systematic antifungal prophylaxis in all patients, an increased awareness about the potential risk of IFI after initiating ibrutinib is warranted, especially when other predisposing factors are associated,” wrote David Ghez, MD, PhD, and colleagues at the Gustave Roussy Institute in Villejuif and other centers in France.

Although ibrutinib, an inhibitor of Bruton’s tyrosine kinase, is generally considered to be less immunosuppressive than other therapies, it was associated with five cases of Pneumocystis jirovecii pneumonia in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib monotherapy in a 2016 report (Blood. 2016;128:1940-3). Of these five patients, four were treatment naive, suggesting that ibrutinib itself could increase risk for invasive opportunistic infections, Dr. Ghez and his colleagues noted.

[email protected]

SOURCE: Ghez D et al., Blood. 2018 Feb 1. doi: 10.1182/blood-2017-11-818286.

Lab mouse

A microRNA-targeting drug could improve the effectiveness of tyrosine kinase inhibitors (TKIs) against chronic myelogenous leukemia (CML), according to preclinical research published in Nature Medicine.

The drug, miristen, targets miR-126, a microRNA expressed in leukemia stem cells (LSCs).

Researchers found that miristen “enhanced the anti-leukemic effects of TKI treatment” in mouse models of CML and “strongly diminished LSC leukemia-initiating capacity.”

“This could be a major breakthrough for people who are in remission for CML because there is always a concern that the disease will come back if TKI treatment is stopped,” said study author Bin Zhang, PhD, of City of Hope Medical Center in Duarte, California.

“Miristen could be the drug that sends the disease into permanent remission.”

For this study, Dr Zhang and her colleagues tested miristen alone and in combination with the TKI nilotinib in mouse models of CML.

The best results were seen in mice treated with miristen and nilotinib. Transplantation of bone marrow cells collected from mice treated with miristen and nilotinib resulted in no sign of leukemia in the healthy recipient mice, meaning all LSCs were eliminated.

The researchers believe miristen simply makes TKIs more effective in killing LSCs. The team also thinks they have discovered the key to the treatment’s success.

The researchers found that endothelial cells in the blood vessels of the bone marrow contain high levels of miR-126. These endothelial cells transfer miR-126 to LSCs, essentially feeding the leukemia what it needs to survive and grow.

The team hypothesized that to eliminate CML, miristen had to lower miR-126 in both the LSCs and the endothelial cells. Testing proved this theory correct.

“What we have discovered is how the microenvironment surrounding the leukemia stem cells supports them and how you need to target miR-126 in the leukemia stem cells and the microenvironment to completely eradicate the disease,” said study author Guido Marcucci, MD, of City of Hope.

“Our current study showed these findings may also apply to other types of leukemia.”

Lab mouse

A microRNA-targeting drug could improve the effectiveness of tyrosine kinase inhibitors (TKIs) against chronic myelogenous leukemia (CML), according to preclinical research published in Nature Medicine.

The drug, miristen, targets miR-126, a microRNA expressed in leukemia stem cells (LSCs).

Researchers found that miristen “enhanced the anti-leukemic effects of TKI treatment” in mouse models of CML and “strongly diminished LSC leukemia-initiating capacity.”

“This could be a major breakthrough for people who are in remission for CML because there is always a concern that the disease will come back if TKI treatment is stopped,” said study author Bin Zhang, PhD, of City of Hope Medical Center in Duarte, California.

“Miristen could be the drug that sends the disease into permanent remission.”

For this study, Dr Zhang and her colleagues tested miristen alone and in combination with the TKI nilotinib in mouse models of CML.

The best results were seen in mice treated with miristen and nilotinib. Transplantation of bone marrow cells collected from mice treated with miristen and nilotinib resulted in no sign of leukemia in the healthy recipient mice, meaning all LSCs were eliminated.

The researchers believe miristen simply makes TKIs more effective in killing LSCs. The team also thinks they have discovered the key to the treatment’s success.

The researchers found that endothelial cells in the blood vessels of the bone marrow contain high levels of miR-126. These endothelial cells transfer miR-126 to LSCs, essentially feeding the leukemia what it needs to survive and grow.

The team hypothesized that to eliminate CML, miristen had to lower miR-126 in both the LSCs and the endothelial cells. Testing proved this theory correct.

“What we have discovered is how the microenvironment surrounding the leukemia stem cells supports them and how you need to target miR-126 in the leukemia stem cells and the microenvironment to completely eradicate the disease,” said study author Guido Marcucci, MD, of City of Hope.

“Our current study showed these findings may also apply to other types of leukemia.”

Lab mouse

A microRNA-targeting drug could improve the effectiveness of tyrosine kinase inhibitors (TKIs) against chronic myelogenous leukemia (CML), according to preclinical research published in Nature Medicine.

The drug, miristen, targets miR-126, a microRNA expressed in leukemia stem cells (LSCs).

Researchers found that miristen “enhanced the anti-leukemic effects of TKI treatment” in mouse models of CML and “strongly diminished LSC leukemia-initiating capacity.”

“This could be a major breakthrough for people who are in remission for CML because there is always a concern that the disease will come back if TKI treatment is stopped,” said study author Bin Zhang, PhD, of City of Hope Medical Center in Duarte, California.

“Miristen could be the drug that sends the disease into permanent remission.”

For this study, Dr Zhang and her colleagues tested miristen alone and in combination with the TKI nilotinib in mouse models of CML.

The best results were seen in mice treated with miristen and nilotinib. Transplantation of bone marrow cells collected from mice treated with miristen and nilotinib resulted in no sign of leukemia in the healthy recipient mice, meaning all LSCs were eliminated.

The researchers believe miristen simply makes TKIs more effective in killing LSCs. The team also thinks they have discovered the key to the treatment’s success.

The researchers found that endothelial cells in the blood vessels of the bone marrow contain high levels of miR-126. These endothelial cells transfer miR-126 to LSCs, essentially feeding the leukemia what it needs to survive and grow.

The team hypothesized that to eliminate CML, miristen had to lower miR-126 in both the LSCs and the endothelial cells. Testing proved this theory correct.

“What we have discovered is how the microenvironment surrounding the leukemia stem cells supports them and how you need to target miR-126 in the leukemia stem cells and the microenvironment to completely eradicate the disease,” said study author Guido Marcucci, MD, of City of Hope.

“Our current study showed these findings may also apply to other types of leukemia.”

ATLANTA – GCLAM – the combined use of granulocyte colony-stimulating factor (G-CSF), cladribine, high-dose cytarabine, and mitoxantrone – was well tolerated and had potent antileukemia activity in a phase 1/2 trial of adults with relapsed/refractory acute myeloid leukemia or high-grade myeloid neoplasms.

Of 40 patients who were treated with GCLAM (with mitoxantrone at the maximum tolerated dose of 16 mg/m² per day as established in phase 1 of the trial), 11 achieved a complete response (CR), and 13 achieved a complete response with incomplete blood count recovery (CRi), for an overall response rate of 60%, Anna B. Halpern, MD, reported at the annual meeting of the American Society of Hematology.

“Nine of the 11 CR patients and 11 of 13 with CRis were negative for minimal residual disease, for an overall MRD-negative CR rate of 23%,” said Dr. Halpern of the University of Washington and the Fred Hutchinson Cancer Research Center, both in Seattle.

Resistant disease occurred in 11 patients, she noted.

Median overall survival was 11.5 months, and the treatment-related mortality (TRM) rate was 5%.

Overall, 21 of 40 patients went to transplant, with a 49% 1-year survival rate, she said.

The patients had a median age of 63 years. Thirty-four had acute myeloid leukemia (AML), and 6 had high-grade myelodysplastic syndrome; 28 had secondary disease. Nineteen had primary refractory disease, 21 had relapsed disease after a median initial CR duration of 12 months, and 7 had prior allogeneic transplant. The median TRM score for all patients was 2.0, indicating a low risk for treatment-related mortality.

“Cytogenetics distribution, based on Medical Research Council criteria, was as expected,” she added.

At the mitoxantrone maximum tolerated dose of 16 mg/m² per day – which was established during phase 1 in 26 patients in whom higher dose levels (18 mg/m² per day) led to dose-limiting encephalopathy and cardiogenic shock – the most common grade 3 or greater adverse events included neutropenic fever, infectious complications, and hypoxia during therapy. This was largely attributed to volume overload and infection, Dr. Halpern said.

“Although three patients did have decreased ejection fraction in cycle 2, this was largely in the setting of sepsis, making the etiology difficult to ascribe to the anthracycline versus sepsis physiology,” she noted.

The median times to an absolute neutrophil count of 500/mcL or greater and platelet count of 50,000/mcL or greater were 29 days each, she noted.

A multivariable analysis controlling for baseline prognostic features showed that the mitoxantrone dose of 16 mg/m² per day was associated with significantly better overall survival, compared with a dose of 10 mg/m² per day used in a historical cohort according to standard GCLAM dosing (hazard ratio for death, 0.45). Additionally, more of those receiving a dose of 16 mg/m² per day went on to transplant (52% vs. 37%), she said. The overall response rate was also higher with the 16-mg/m² dose, but the difference was not statistically significant (odds ratio, 1.87).

“Further, the outcomes appear to be as good or better with GCLAM with mitoxantrone at 16 mg/m² compared to other salvage regimens used at our institution, including decitabine priming plus mitoxantrone, etoposide, and cytarabine [d/MEC] and G-CSF with clofarabine and high-dose cytarabine [GCLAC],” she said, noting that the examination is currently ongoing in a larger sample.

The initial analysis, however, showed that, after controlling for age, cytogenetic risk, first CR duration, and prior hematopoietic cell transplant, overall response and overall survival rates were better with GCLAM than with d/MEC (OR, 3.23; HR for death, 0.64) and that the overall response rate was similar between GCLAM and GCLAC (OR, 1.75), she said.

The findings are encouraging because outcomes with standard chemotherapies for relapsed/refractory myeloid neoplasms are poor, with complete remission rates rarely exceeding 15%-20%, Dr. Halpern said.

The current study was undertaken based on promising results from a previous phase 2 study in poor-risk relapsed/refractory AML, which also showed encouraging activity with GCLAM and based on data suggesting benefit with escalated doses of anthracyclines in AML, she explained.

Patients 18 years and older were eligible if they had adequate organ function and a TRM score of 6.9 or lower, which corresponds to a predicted 28-day mortality of no more than 6.9% with standard induction chemotherapy. Those with uncontrolled infection or concomitant illness with expected survival of less than 1 year were excluded.

The phase 1 dose escalation involved cohorts of 6-12 patients who were assigned to receive mitoxantrone dose levels of 12, 14, 16, or 18 mg/m² per day on days 1-3. The doses of the remaining drugs in the combination were fixed at 300 mcg or 480 mcg of G-CSF on days 0-5, 5 mg/m² of cladribine on days 1-5, and 2 mg/m² of cytarabine on days 1-5.

“All patients received GCLAM induction at their assigned mitoxantrone dose level. If CR wasn’t achieved with cycle 1, a second identical course of GCLAM was given,” Dr. Halpern explained, noting that patients with resistant disease after 2 cycles were taken off the study.

If CR or CRi was achieved within 1-2 cycles of induction, up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed, and responders could proceed with transplant at any time.

In phase 2, patients received the maximum tolerated dose of mitoxantrone (16mg/m² per day), as defined in phase 1.

“Relapsed and refractory AML and high grade myeloid neoplasms are a challenging disease to treat. With an overall response rate of 60%, this regimen showed efficacy in a heavily pretreated patient population,” Dr. Halpern said. “And many of the responders were able to go on to receive a stem cell transplant, the only known curative option in this situation.”

A follow-up study is currently exploring the relative value of decitabine priming followed by GCLAM in this setting, she said.

Dr. Halpern reported having no relevant financial disclosures.

[email protected]

SOURCE: Halpern AB et al. ASH 2017, Abstract 149

ATLANTA – GCLAM – the combined use of granulocyte colony-stimulating factor (G-CSF), cladribine, high-dose cytarabine, and mitoxantrone – was well tolerated and had potent antileukemia activity in a phase 1/2 trial of adults with relapsed/refractory acute myeloid leukemia or high-grade myeloid neoplasms.

Of 40 patients who were treated with GCLAM (with mitoxantrone at the maximum tolerated dose of 16 mg/m² per day as established in phase 1 of the trial), 11 achieved a complete response (CR), and 13 achieved a complete response with incomplete blood count recovery (CRi), for an overall response rate of 60%, Anna B. Halpern, MD, reported at the annual meeting of the American Society of Hematology.

“Nine of the 11 CR patients and 11 of 13 with CRis were negative for minimal residual disease, for an overall MRD-negative CR rate of 23%,” said Dr. Halpern of the University of Washington and the Fred Hutchinson Cancer Research Center, both in Seattle.

Resistant disease occurred in 11 patients, she noted.

Median overall survival was 11.5 months, and the treatment-related mortality (TRM) rate was 5%.

Overall, 21 of 40 patients went to transplant, with a 49% 1-year survival rate, she said.

The patients had a median age of 63 years. Thirty-four had acute myeloid leukemia (AML), and 6 had high-grade myelodysplastic syndrome; 28 had secondary disease. Nineteen had primary refractory disease, 21 had relapsed disease after a median initial CR duration of 12 months, and 7 had prior allogeneic transplant. The median TRM score for all patients was 2.0, indicating a low risk for treatment-related mortality.

“Cytogenetics distribution, based on Medical Research Council criteria, was as expected,” she added.

At the mitoxantrone maximum tolerated dose of 16 mg/m² per day – which was established during phase 1 in 26 patients in whom higher dose levels (18 mg/m² per day) led to dose-limiting encephalopathy and cardiogenic shock – the most common grade 3 or greater adverse events included neutropenic fever, infectious complications, and hypoxia during therapy. This was largely attributed to volume overload and infection, Dr. Halpern said.

“Although three patients did have decreased ejection fraction in cycle 2, this was largely in the setting of sepsis, making the etiology difficult to ascribe to the anthracycline versus sepsis physiology,” she noted.

The median times to an absolute neutrophil count of 500/mcL or greater and platelet count of 50,000/mcL or greater were 29 days each, she noted.

A multivariable analysis controlling for baseline prognostic features showed that the mitoxantrone dose of 16 mg/m² per day was associated with significantly better overall survival, compared with a dose of 10 mg/m² per day used in a historical cohort according to standard GCLAM dosing (hazard ratio for death, 0.45). Additionally, more of those receiving a dose of 16 mg/m² per day went on to transplant (52% vs. 37%), she said. The overall response rate was also higher with the 16-mg/m² dose, but the difference was not statistically significant (odds ratio, 1.87).

“Further, the outcomes appear to be as good or better with GCLAM with mitoxantrone at 16 mg/m² compared to other salvage regimens used at our institution, including decitabine priming plus mitoxantrone, etoposide, and cytarabine [d/MEC] and G-CSF with clofarabine and high-dose cytarabine [GCLAC],” she said, noting that the examination is currently ongoing in a larger sample.

The initial analysis, however, showed that, after controlling for age, cytogenetic risk, first CR duration, and prior hematopoietic cell transplant, overall response and overall survival rates were better with GCLAM than with d/MEC (OR, 3.23; HR for death, 0.64) and that the overall response rate was similar between GCLAM and GCLAC (OR, 1.75), she said.

The findings are encouraging because outcomes with standard chemotherapies for relapsed/refractory myeloid neoplasms are poor, with complete remission rates rarely exceeding 15%-20%, Dr. Halpern said.

The current study was undertaken based on promising results from a previous phase 2 study in poor-risk relapsed/refractory AML, which also showed encouraging activity with GCLAM and based on data suggesting benefit with escalated doses of anthracyclines in AML, she explained.

Patients 18 years and older were eligible if they had adequate organ function and a TRM score of 6.9 or lower, which corresponds to a predicted 28-day mortality of no more than 6.9% with standard induction chemotherapy. Those with uncontrolled infection or concomitant illness with expected survival of less than 1 year were excluded.

The phase 1 dose escalation involved cohorts of 6-12 patients who were assigned to receive mitoxantrone dose levels of 12, 14, 16, or 18 mg/m² per day on days 1-3. The doses of the remaining drugs in the combination were fixed at 300 mcg or 480 mcg of G-CSF on days 0-5, 5 mg/m² of cladribine on days 1-5, and 2 mg/m² of cytarabine on days 1-5.

“All patients received GCLAM induction at their assigned mitoxantrone dose level. If CR wasn’t achieved with cycle 1, a second identical course of GCLAM was given,” Dr. Halpern explained, noting that patients with resistant disease after 2 cycles were taken off the study.

If CR or CRi was achieved within 1-2 cycles of induction, up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed, and responders could proceed with transplant at any time.

In phase 2, patients received the maximum tolerated dose of mitoxantrone (16mg/m² per day), as defined in phase 1.

“Relapsed and refractory AML and high grade myeloid neoplasms are a challenging disease to treat. With an overall response rate of 60%, this regimen showed efficacy in a heavily pretreated patient population,” Dr. Halpern said. “And many of the responders were able to go on to receive a stem cell transplant, the only known curative option in this situation.”

A follow-up study is currently exploring the relative value of decitabine priming followed by GCLAM in this setting, she said.

Dr. Halpern reported having no relevant financial disclosures.

[email protected]

SOURCE: Halpern AB et al. ASH 2017, Abstract 149

ATLANTA – GCLAM – the combined use of granulocyte colony-stimulating factor (G-CSF), cladribine, high-dose cytarabine, and mitoxantrone – was well tolerated and had potent antileukemia activity in a phase 1/2 trial of adults with relapsed/refractory acute myeloid leukemia or high-grade myeloid neoplasms.

Of 40 patients who were treated with GCLAM (with mitoxantrone at the maximum tolerated dose of 16 mg/m² per day as established in phase 1 of the trial), 11 achieved a complete response (CR), and 13 achieved a complete response with incomplete blood count recovery (CRi), for an overall response rate of 60%, Anna B. Halpern, MD, reported at the annual meeting of the American Society of Hematology.

“Nine of the 11 CR patients and 11 of 13 with CRis were negative for minimal residual disease, for an overall MRD-negative CR rate of 23%,” said Dr. Halpern of the University of Washington and the Fred Hutchinson Cancer Research Center, both in Seattle.

Resistant disease occurred in 11 patients, she noted.

Median overall survival was 11.5 months, and the treatment-related mortality (TRM) rate was 5%.

Overall, 21 of 40 patients went to transplant, with a 49% 1-year survival rate, she said.

The patients had a median age of 63 years. Thirty-four had acute myeloid leukemia (AML), and 6 had high-grade myelodysplastic syndrome; 28 had secondary disease. Nineteen had primary refractory disease, 21 had relapsed disease after a median initial CR duration of 12 months, and 7 had prior allogeneic transplant. The median TRM score for all patients was 2.0, indicating a low risk for treatment-related mortality.

“Cytogenetics distribution, based on Medical Research Council criteria, was as expected,” she added.

At the mitoxantrone maximum tolerated dose of 16 mg/m² per day – which was established during phase 1 in 26 patients in whom higher dose levels (18 mg/m² per day) led to dose-limiting encephalopathy and cardiogenic shock – the most common grade 3 or greater adverse events included neutropenic fever, infectious complications, and hypoxia during therapy. This was largely attributed to volume overload and infection, Dr. Halpern said.

“Although three patients did have decreased ejection fraction in cycle 2, this was largely in the setting of sepsis, making the etiology difficult to ascribe to the anthracycline versus sepsis physiology,” she noted.

The median times to an absolute neutrophil count of 500/mcL or greater and platelet count of 50,000/mcL or greater were 29 days each, she noted.

A multivariable analysis controlling for baseline prognostic features showed that the mitoxantrone dose of 16 mg/m² per day was associated with significantly better overall survival, compared with a dose of 10 mg/m² per day used in a historical cohort according to standard GCLAM dosing (hazard ratio for death, 0.45). Additionally, more of those receiving a dose of 16 mg/m² per day went on to transplant (52% vs. 37%), she said. The overall response rate was also higher with the 16-mg/m² dose, but the difference was not statistically significant (odds ratio, 1.87).

“Further, the outcomes appear to be as good or better with GCLAM with mitoxantrone at 16 mg/m² compared to other salvage regimens used at our institution, including decitabine priming plus mitoxantrone, etoposide, and cytarabine [d/MEC] and G-CSF with clofarabine and high-dose cytarabine [GCLAC],” she said, noting that the examination is currently ongoing in a larger sample.

The initial analysis, however, showed that, after controlling for age, cytogenetic risk, first CR duration, and prior hematopoietic cell transplant, overall response and overall survival rates were better with GCLAM than with d/MEC (OR, 3.23; HR for death, 0.64) and that the overall response rate was similar between GCLAM and GCLAC (OR, 1.75), she said.

The findings are encouraging because outcomes with standard chemotherapies for relapsed/refractory myeloid neoplasms are poor, with complete remission rates rarely exceeding 15%-20%, Dr. Halpern said.

The current study was undertaken based on promising results from a previous phase 2 study in poor-risk relapsed/refractory AML, which also showed encouraging activity with GCLAM and based on data suggesting benefit with escalated doses of anthracyclines in AML, she explained.

Patients 18 years and older were eligible if they had adequate organ function and a TRM score of 6.9 or lower, which corresponds to a predicted 28-day mortality of no more than 6.9% with standard induction chemotherapy. Those with uncontrolled infection or concomitant illness with expected survival of less than 1 year were excluded.

The phase 1 dose escalation involved cohorts of 6-12 patients who were assigned to receive mitoxantrone dose levels of 12, 14, 16, or 18 mg/m² per day on days 1-3. The doses of the remaining drugs in the combination were fixed at 300 mcg or 480 mcg of G-CSF on days 0-5, 5 mg/m² of cladribine on days 1-5, and 2 mg/m² of cytarabine on days 1-5.

“All patients received GCLAM induction at their assigned mitoxantrone dose level. If CR wasn’t achieved with cycle 1, a second identical course of GCLAM was given,” Dr. Halpern explained, noting that patients with resistant disease after 2 cycles were taken off the study.

If CR or CRi was achieved within 1-2 cycles of induction, up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed, and responders could proceed with transplant at any time.

In phase 2, patients received the maximum tolerated dose of mitoxantrone (16mg/m² per day), as defined in phase 1.

“Relapsed and refractory AML and high grade myeloid neoplasms are a challenging disease to treat. With an overall response rate of 60%, this regimen showed efficacy in a heavily pretreated patient population,” Dr. Halpern said. “And many of the responders were able to go on to receive a stem cell transplant, the only known curative option in this situation.”

A follow-up study is currently exploring the relative value of decitabine priming followed by GCLAM in this setting, she said.

Dr. Halpern reported having no relevant financial disclosures.

[email protected]

SOURCE: Halpern AB et al. ASH 2017, Abstract 149

Micrograph showing ALL

Researchers say they have developed a technique that can help them determine, at diagnosis, whether children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) will relapse after treatment.

The method involves examining individual leukemia cells using mass cytometry.

In looking at the cells’ stage of development and signaling behavior, the researchers were able to identify a subset of malignant cells that predispose a patient to relapse.

The team described this method, which they termed “developmentally dependent predictor of relapse (DDPR),” in Nature Medicine.

Prior research suggested relapse may be driven by treatment-resistant cells that are present from the beginning of disease development.

“We wondered, can we identify those cells at the time the patient first presents to the clinic, and can we treat patients with a specific therapy to target them?” said study author Kara Davis, DO, of Stanford University in California.

Dr Davis and her colleagues used mass cytometry to analyze diagnostic bone marrow samples from 60 patients with BCP-ALL.

To pinpoint the problematic cells among the millions of cells in each patient’s sample, the researchers had to figure out how to organize the data.

“Every patient has vastly different features to their cancer,” Dr Davis said, “and we had to ask, ‘Is there any common thread between them?’”

The solution, the researchers found, was to match BCP-ALL cells and healthy B cells according to their developmental states, comparing the leukemic cells to the healthy cells.

The comparison revealed 6 features of leukemic cell populations that were associated with relapse.

Broadly, the features suggested that pro-BII cells with activated mTOR signaling were associated with relapse, as were pre-BI cells with activated and unresponsive pre-B-cell receptor signaling.

“We do not understand the mechanisms by which malignant cells from the pro-BII and pre-BI stages of development resist treatment,” Dr Davis noted.

However, she and her colleagues were able to show the leukemic cell features identified by DDPR could predict relapse in the BCP-ALL patients.

Of the 60 patients analyzed, there were 54 with at least 3 years of follow-up. The researchers divided these patients into a training cohort (n=44) and a validation cohort (n=10).

The team used an integrated cumulative/dynamic area under the curve (iAUC) and a C-statistic to assess DDPR performance in both cohorts.

In the training cohort, DDPR had an iAUC value of 0.92 and a C-statistic of 0.87. In the validation cohort, DDPR had an iAUC value of 0.85 and a C-statistic of 0.87.

The researchers also said DDPR “performed well” in predicting relapse-free survival in a retrospective analysis of both cohorts (P = 2.8 × 10⁻⁷).

Now, the researchers plan to validate DDPR in a larger number of patients and evaluate whether the same general approach could predict relapse in other cancers.

Micrograph showing ALL

Researchers say they have developed a technique that can help them determine, at diagnosis, whether children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) will relapse after treatment.

The method involves examining individual leukemia cells using mass cytometry.

In looking at the cells’ stage of development and signaling behavior, the researchers were able to identify a subset of malignant cells that predispose a patient to relapse.

The team described this method, which they termed “developmentally dependent predictor of relapse (DDPR),” in Nature Medicine.

Prior research suggested relapse may be driven by treatment-resistant cells that are present from the beginning of disease development.

“We wondered, can we identify those cells at the time the patient first presents to the clinic, and can we treat patients with a specific therapy to target them?” said study author Kara Davis, DO, of Stanford University in California.

Dr Davis and her colleagues used mass cytometry to analyze diagnostic bone marrow samples from 60 patients with BCP-ALL.

To pinpoint the problematic cells among the millions of cells in each patient’s sample, the researchers had to figure out how to organize the data.

“Every patient has vastly different features to their cancer,” Dr Davis said, “and we had to ask, ‘Is there any common thread between them?’”

The solution, the researchers found, was to match BCP-ALL cells and healthy B cells according to their developmental states, comparing the leukemic cells to the healthy cells.

The comparison revealed 6 features of leukemic cell populations that were associated with relapse.

Broadly, the features suggested that pro-BII cells with activated mTOR signaling were associated with relapse, as were pre-BI cells with activated and unresponsive pre-B-cell receptor signaling.

“We do not understand the mechanisms by which malignant cells from the pro-BII and pre-BI stages of development resist treatment,” Dr Davis noted.

However, she and her colleagues were able to show the leukemic cell features identified by DDPR could predict relapse in the BCP-ALL patients.

Of the 60 patients analyzed, there were 54 with at least 3 years of follow-up. The researchers divided these patients into a training cohort (n=44) and a validation cohort (n=10).

The team used an integrated cumulative/dynamic area under the curve (iAUC) and a C-statistic to assess DDPR performance in both cohorts.

In the training cohort, DDPR had an iAUC value of 0.92 and a C-statistic of 0.87. In the validation cohort, DDPR had an iAUC value of 0.85 and a C-statistic of 0.87.

The researchers also said DDPR “performed well” in predicting relapse-free survival in a retrospective analysis of both cohorts (P = 2.8 × 10⁻⁷).

Now, the researchers plan to validate DDPR in a larger number of patients and evaluate whether the same general approach could predict relapse in other cancers.

Micrograph showing ALL

Researchers say they have developed a technique that can help them determine, at diagnosis, whether children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) will relapse after treatment.

The method involves examining individual leukemia cells using mass cytometry.

In looking at the cells’ stage of development and signaling behavior, the researchers were able to identify a subset of malignant cells that predispose a patient to relapse.

The team described this method, which they termed “developmentally dependent predictor of relapse (DDPR),” in Nature Medicine.

Prior research suggested relapse may be driven by treatment-resistant cells that are present from the beginning of disease development.

“We wondered, can we identify those cells at the time the patient first presents to the clinic, and can we treat patients with a specific therapy to target them?” said study author Kara Davis, DO, of Stanford University in California.

Dr Davis and her colleagues used mass cytometry to analyze diagnostic bone marrow samples from 60 patients with BCP-ALL.

To pinpoint the problematic cells among the millions of cells in each patient’s sample, the researchers had to figure out how to organize the data.

“Every patient has vastly different features to their cancer,” Dr Davis said, “and we had to ask, ‘Is there any common thread between them?’”

The solution, the researchers found, was to match BCP-ALL cells and healthy B cells according to their developmental states, comparing the leukemic cells to the healthy cells.

The comparison revealed 6 features of leukemic cell populations that were associated with relapse.

Broadly, the features suggested that pro-BII cells with activated mTOR signaling were associated with relapse, as were pre-BI cells with activated and unresponsive pre-B-cell receptor signaling.

“We do not understand the mechanisms by which malignant cells from the pro-BII and pre-BI stages of development resist treatment,” Dr Davis noted.

However, she and her colleagues were able to show the leukemic cell features identified by DDPR could predict relapse in the BCP-ALL patients.

Of the 60 patients analyzed, there were 54 with at least 3 years of follow-up. The researchers divided these patients into a training cohort (n=44) and a validation cohort (n=10).

The team used an integrated cumulative/dynamic area under the curve (iAUC) and a C-statistic to assess DDPR performance in both cohorts.

In the training cohort, DDPR had an iAUC value of 0.92 and a C-statistic of 0.87. In the validation cohort, DDPR had an iAUC value of 0.85 and a C-statistic of 0.87.

The researchers also said DDPR “performed well” in predicting relapse-free survival in a retrospective analysis of both cohorts (P = 2.8 × 10⁻⁷).

Now, the researchers plan to validate DDPR in a larger number of patients and evaluate whether the same general approach could predict relapse in other cancers.

Parinda A. Mehta, MD

SALT LAKE CITY—A “risk-adjusted” approach leads to “excellent” survival in patients with Fanconi anemia (FA) undergoing alternative donor hematopoietic stem cell transplant (HSCT), according to a speaker at the 2018 BMT Tandem Meetings.

All FA patients who received personalized doses of busulfan in place of total body irradiation (TBI) were alive and disease-free after undergoing HSCT for bone marrow failure or myelodysplastic syndrome (MDS).

None of the patients developed graft-vs-host disease (GVHD), and the most common toxicity was viral infection.

Parinda A. Mehta, MD, of Cincinnati Children’s Hospital Medical Center in Ohio, presented these results at this year’s BMT Tandem Meetings as abstract 109.*

“We all know that inherent chemotherapy and radiation sensitivity makes transplant for patients with Fanconi anemia quite challenging,” Dr Mehta began. “In our recently published, prospective, multi-institutional study, we showed excellent outcomes of alternative donor transplant in patients with Fanconi anemia without using radiation.”

“In that study,** TBI was replaced by pharmacokinetically adjusted busulfan. It proved that, yes, we can do alternative donor transplant successfully without radiation by showing an overall survival of 80% for a total of 45 patients. We were quite ecstatic to see these numbers.”

The study also showed that younger patients fared better with this regimen, and younger patients did best with the lowest dose of busulfan tested (0.6 mg/kg vs 0.8 to 1.0 mg/kg). In addition, patients who underwent HSCT for bone marrow failure had better outcomes than patients who had MDS.

This led Dr Mehta and her colleagues to hypothesize that adjusting busulfan dosing based on a patient’s age and disease status at HSCT could minimize toxicity and improve outcomes.

Patients

The researchers tested their theory in 22 FA patients. They had a median age of 7 (range, 4-27), and most (n=13) were female.

Twelve patients had pancytopenia, 6 had severe single-lineage cytopenia, 3 had low-grade MDS, and 1 patient had acute myeloid leukemia (AML).

Eighteen patients had a history of transfusions, and 3 had a history of androgen use.

Treatment

The preparative regimen consisted of 4 doses of busulfan (every 12 hours on day -7 to -6), followed by cyclophosphamide at 10 mg/kg/day (on day -5 to -2), fludarabine at 35 mg/m²/day (on day -5 to -2), and rabbit antithymocyte globulin at 2.5 mg/kg/day (on day -5 to -2).

Busulfan doses were adjusted according to age and disease status.

Children (age 18 and younger) with bone marrow failure received busulfan at 0.6 to 0.8 mg/kg. Children with MDS/AML received busulfan at 0.8 to 1.0 mg/kg. Adults (19 and older) received the lowest dose of busulfan—0.4 mg/kg—regardless of disease status.

“At the first sight, this will look counterintuitive . . . ,” Dr Mehta said. “However, based on our previous experience, in general and also from results of our previous study, this was specifically designed to avoid upfront TRM [transplant-related mortality] for these adult patients.”

All 22 patients received CD34-selected, T-cell-depleted peripheral blood stem cells from unrelated donors. Eleven patients received a fully matched graft (10/10), 8 patients had a 9/10 match, and 3 had an 8/10 match.

The median number of CD34+ cells/kg was 23.9 x 10⁶ (range, 4.9-76.6), and the median number of CD3 cells/kg was 1 x 10⁴ (range, 0.003-3.1).

T-cell depletion was the only GVHD prophylaxis used.

Patients with MDS/AML could receive azacitidine at day 42 after HSCT, an option intended to prevent relapse in these patients.

Toxicity

There were no cases of acute or chronic GVHD.

Toxicities included infections (n=24), oral mucositis (n=14), hyperbilirubinemia (n=2), pulmonary hemorrhage (n=1), and sinusoidal obstruction syndrome (n=1).

There were 20 viral infections, 4 bacterial infections, and no fungal infections. Viral infections included BK virus (n=7), cytomegalovirus (n=6), Epstein-Barr virus (n=6), and adenovirus (n=1).

Dr Mehta noted that viral infections are “not unexpected in a T-cell-depleted graft setting.”

“Because we know this complication [can occur], and we worry about our patients, one of the things that, in recent years, we have done is, we manufacture viral-specific CTLs [cytotoxic T lymphocytes] for all of these patients ahead of time whenever possible,” she said.

“To give you an example, 19 out of these 20 patients’ viral infections—or rather, viremias—are completely under control with the use of either antivirals or donor-specific CTLs, including a third-party CTL in one of the patients.”

Response and survival

All 22 patients engrafted. The median time to neutrophil engraftment was 9 days (range, 8-10), and the median time to platelet engraftment was 16 days (range, 11-40).

Twenty-one of the 22 patients (95%) were alive and disease-free at last follow-up. The median follow-up was 21 months (range, 6-44).

The single AML patient achieved remission but died of post-transplant lymphoproliferative disorder (PTLD) on day 202 after HSCT. Dr Mehta said this was due to partial loss of follow-up and noncompliance with medical recommendations during PTLD treatment.

The AML patient also had “significant upfront toxicity” but “recovered very nicely,” according to Dr Mehta. He had severe mucositis, herpetic stomatitis, and sinusoidal obstruction syndrome that responded to defibrotide.

“Overall, we are quite excited to see 95% overall survival for this cohort and conclude that the current risk-adjusted approach leads to excellent overall survival and disease-free survival in patients undergoing alternative donor transplant either for marrow failure or MDS/AML,” Dr Mehta said.

“Enrollment is ongoing, and we hope to see continued success in patients with MDS/AML as well as in adult patients.”

*Data in the abstract differ from the presentation.

**Mehta PA et al. Radiation-free, alternative donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Blood 2017; doi: https://doi.org/10.1182/blood-2016-09-743112.

Parinda A. Mehta, MD

SALT LAKE CITY—A “risk-adjusted” approach leads to “excellent” survival in patients with Fanconi anemia (FA) undergoing alternative donor hematopoietic stem cell transplant (HSCT), according to a speaker at the 2018 BMT Tandem Meetings.

All FA patients who received personalized doses of busulfan in place of total body irradiation (TBI) were alive and disease-free after undergoing HSCT for bone marrow failure or myelodysplastic syndrome (MDS).

None of the patients developed graft-vs-host disease (GVHD), and the most common toxicity was viral infection.

Parinda A. Mehta, MD, of Cincinnati Children’s Hospital Medical Center in Ohio, presented these results at this year’s BMT Tandem Meetings as abstract 109.*

“We all know that inherent chemotherapy and radiation sensitivity makes transplant for patients with Fanconi anemia quite challenging,” Dr Mehta began. “In our recently published, prospective, multi-institutional study, we showed excellent outcomes of alternative donor transplant in patients with Fanconi anemia without using radiation.”

“In that study,** TBI was replaced by pharmacokinetically adjusted busulfan. It proved that, yes, we can do alternative donor transplant successfully without radiation by showing an overall survival of 80% for a total of 45 patients. We were quite ecstatic to see these numbers.”

The study also showed that younger patients fared better with this regimen, and younger patients did best with the lowest dose of busulfan tested (0.6 mg/kg vs 0.8 to 1.0 mg/kg). In addition, patients who underwent HSCT for bone marrow failure had better outcomes than patients who had MDS.

This led Dr Mehta and her colleagues to hypothesize that adjusting busulfan dosing based on a patient’s age and disease status at HSCT could minimize toxicity and improve outcomes.

Patients

The researchers tested their theory in 22 FA patients. They had a median age of 7 (range, 4-27), and most (n=13) were female.

Twelve patients had pancytopenia, 6 had severe single-lineage cytopenia, 3 had low-grade MDS, and 1 patient had acute myeloid leukemia (AML).

Eighteen patients had a history of transfusions, and 3 had a history of androgen use.

Treatment

The preparative regimen consisted of 4 doses of busulfan (every 12 hours on day -7 to -6), followed by cyclophosphamide at 10 mg/kg/day (on day -5 to -2), fludarabine at 35 mg/m²/day (on day -5 to -2), and rabbit antithymocyte globulin at 2.5 mg/kg/day (on day -5 to -2).

Busulfan doses were adjusted according to age and disease status.

Children (age 18 and younger) with bone marrow failure received busulfan at 0.6 to 0.8 mg/kg. Children with MDS/AML received busulfan at 0.8 to 1.0 mg/kg. Adults (19 and older) received the lowest dose of busulfan—0.4 mg/kg—regardless of disease status.

“At the first sight, this will look counterintuitive . . . ,” Dr Mehta said. “However, based on our previous experience, in general and also from results of our previous study, this was specifically designed to avoid upfront TRM [transplant-related mortality] for these adult patients.”

All 22 patients received CD34-selected, T-cell-depleted peripheral blood stem cells from unrelated donors. Eleven patients received a fully matched graft (10/10), 8 patients had a 9/10 match, and 3 had an 8/10 match.

The median number of CD34+ cells/kg was 23.9 x 10⁶ (range, 4.9-76.6), and the median number of CD3 cells/kg was 1 x 10⁴ (range, 0.003-3.1).

T-cell depletion was the only GVHD prophylaxis used.

Patients with MDS/AML could receive azacitidine at day 42 after HSCT, an option intended to prevent relapse in these patients.

Toxicity

There were no cases of acute or chronic GVHD.

Toxicities included infections (n=24), oral mucositis (n=14), hyperbilirubinemia (n=2), pulmonary hemorrhage (n=1), and sinusoidal obstruction syndrome (n=1).

There were 20 viral infections, 4 bacterial infections, and no fungal infections. Viral infections included BK virus (n=7), cytomegalovirus (n=6), Epstein-Barr virus (n=6), and adenovirus (n=1).

Dr Mehta noted that viral infections are “not unexpected in a T-cell-depleted graft setting.”

“Because we know this complication [can occur], and we worry about our patients, one of the things that, in recent years, we have done is, we manufacture viral-specific CTLs [cytotoxic T lymphocytes] for all of these patients ahead of time whenever possible,” she said.

“To give you an example, 19 out of these 20 patients’ viral infections—or rather, viremias—are completely under control with the use of either antivirals or donor-specific CTLs, including a third-party CTL in one of the patients.”

Response and survival

All 22 patients engrafted. The median time to neutrophil engraftment was 9 days (range, 8-10), and the median time to platelet engraftment was 16 days (range, 11-40).

Twenty-one of the 22 patients (95%) were alive and disease-free at last follow-up. The median follow-up was 21 months (range, 6-44).

The single AML patient achieved remission but died of post-transplant lymphoproliferative disorder (PTLD) on day 202 after HSCT. Dr Mehta said this was due to partial loss of follow-up and noncompliance with medical recommendations during PTLD treatment.

The AML patient also had “significant upfront toxicity” but “recovered very nicely,” according to Dr Mehta. He had severe mucositis, herpetic stomatitis, and sinusoidal obstruction syndrome that responded to defibrotide.

“Overall, we are quite excited to see 95% overall survival for this cohort and conclude that the current risk-adjusted approach leads to excellent overall survival and disease-free survival in patients undergoing alternative donor transplant either for marrow failure or MDS/AML,” Dr Mehta said.

“Enrollment is ongoing, and we hope to see continued success in patients with MDS/AML as well as in adult patients.”

*Data in the abstract differ from the presentation.

**Mehta PA et al. Radiation-free, alternative donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Blood 2017; doi: https://doi.org/10.1182/blood-2016-09-743112.

Parinda A. Mehta, MD

SALT LAKE CITY—A “risk-adjusted” approach leads to “excellent” survival in patients with Fanconi anemia (FA) undergoing alternative donor hematopoietic stem cell transplant (HSCT), according to a speaker at the 2018 BMT Tandem Meetings.

All FA patients who received personalized doses of busulfan in place of total body irradiation (TBI) were alive and disease-free after undergoing HSCT for bone marrow failure or myelodysplastic syndrome (MDS).

None of the patients developed graft-vs-host disease (GVHD), and the most common toxicity was viral infection.

Parinda A. Mehta, MD, of Cincinnati Children’s Hospital Medical Center in Ohio, presented these results at this year’s BMT Tandem Meetings as abstract 109.*

“We all know that inherent chemotherapy and radiation sensitivity makes transplant for patients with Fanconi anemia quite challenging,” Dr Mehta began. “In our recently published, prospective, multi-institutional study, we showed excellent outcomes of alternative donor transplant in patients with Fanconi anemia without using radiation.”

“In that study,** TBI was replaced by pharmacokinetically adjusted busulfan. It proved that, yes, we can do alternative donor transplant successfully without radiation by showing an overall survival of 80% for a total of 45 patients. We were quite ecstatic to see these numbers.”

The study also showed that younger patients fared better with this regimen, and younger patients did best with the lowest dose of busulfan tested (0.6 mg/kg vs 0.8 to 1.0 mg/kg). In addition, patients who underwent HSCT for bone marrow failure had better outcomes than patients who had MDS.

This led Dr Mehta and her colleagues to hypothesize that adjusting busulfan dosing based on a patient’s age and disease status at HSCT could minimize toxicity and improve outcomes.

Patients

The researchers tested their theory in 22 FA patients. They had a median age of 7 (range, 4-27), and most (n=13) were female.

Twelve patients had pancytopenia, 6 had severe single-lineage cytopenia, 3 had low-grade MDS, and 1 patient had acute myeloid leukemia (AML).

Eighteen patients had a history of transfusions, and 3 had a history of androgen use.

Treatment

The preparative regimen consisted of 4 doses of busulfan (every 12 hours on day -7 to -6), followed by cyclophosphamide at 10 mg/kg/day (on day -5 to -2), fludarabine at 35 mg/m²/day (on day -5 to -2), and rabbit antithymocyte globulin at 2.5 mg/kg/day (on day -5 to -2).

Busulfan doses were adjusted according to age and disease status.

Children (age 18 and younger) with bone marrow failure received busulfan at 0.6 to 0.8 mg/kg. Children with MDS/AML received busulfan at 0.8 to 1.0 mg/kg. Adults (19 and older) received the lowest dose of busulfan—0.4 mg/kg—regardless of disease status.

“At the first sight, this will look counterintuitive . . . ,” Dr Mehta said. “However, based on our previous experience, in general and also from results of our previous study, this was specifically designed to avoid upfront TRM [transplant-related mortality] for these adult patients.”

All 22 patients received CD34-selected, T-cell-depleted peripheral blood stem cells from unrelated donors. Eleven patients received a fully matched graft (10/10), 8 patients had a 9/10 match, and 3 had an 8/10 match.

The median number of CD34+ cells/kg was 23.9 x 10⁶ (range, 4.9-76.6), and the median number of CD3 cells/kg was 1 x 10⁴ (range, 0.003-3.1).

T-cell depletion was the only GVHD prophylaxis used.

Patients with MDS/AML could receive azacitidine at day 42 after HSCT, an option intended to prevent relapse in these patients.

Toxicity

There were no cases of acute or chronic GVHD.

Toxicities included infections (n=24), oral mucositis (n=14), hyperbilirubinemia (n=2), pulmonary hemorrhage (n=1), and sinusoidal obstruction syndrome (n=1).

There were 20 viral infections, 4 bacterial infections, and no fungal infections. Viral infections included BK virus (n=7), cytomegalovirus (n=6), Epstein-Barr virus (n=6), and adenovirus (n=1).

Dr Mehta noted that viral infections are “not unexpected in a T-cell-depleted graft setting.”

“Because we know this complication [can occur], and we worry about our patients, one of the things that, in recent years, we have done is, we manufacture viral-specific CTLs [cytotoxic T lymphocytes] for all of these patients ahead of time whenever possible,” she said.

“To give you an example, 19 out of these 20 patients’ viral infections—or rather, viremias—are completely under control with the use of either antivirals or donor-specific CTLs, including a third-party CTL in one of the patients.”

Response and survival

All 22 patients engrafted. The median time to neutrophil engraftment was 9 days (range, 8-10), and the median time to platelet engraftment was 16 days (range, 11-40).

Twenty-one of the 22 patients (95%) were alive and disease-free at last follow-up. The median follow-up was 21 months (range, 6-44).

The single AML patient achieved remission but died of post-transplant lymphoproliferative disorder (PTLD) on day 202 after HSCT. Dr Mehta said this was due to partial loss of follow-up and noncompliance with medical recommendations during PTLD treatment.

The AML patient also had “significant upfront toxicity” but “recovered very nicely,” according to Dr Mehta. He had severe mucositis, herpetic stomatitis, and sinusoidal obstruction syndrome that responded to defibrotide.

“Overall, we are quite excited to see 95% overall survival for this cohort and conclude that the current risk-adjusted approach leads to excellent overall survival and disease-free survival in patients undergoing alternative donor transplant either for marrow failure or MDS/AML,” Dr Mehta said.

“Enrollment is ongoing, and we hope to see continued success in patients with MDS/AML as well as in adult patients.”

*Data in the abstract differ from the presentation.

**Mehta PA et al. Radiation-free, alternative donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Blood 2017; doi: https://doi.org/10.1182/blood-2016-09-743112.

Amandeep Godara, MD

SALT LAKE CITY—Results of a large, retrospective analysis support the notion that patients who receive cord blood (CB) transplants have a higher risk of infection than other hematopoietic stem cell transplant (HSCT) recipients.

Investigators found that CB recipients had a significantly higher risk of bacterial, viral, and fungal infections in the early post-transplant period than patients who received peripheral blood (PB) or bone marrow (BM) transplants.

In addition, CB recipients had longer hospital stays, higher inpatient costs, and greater inpatient mortality than PB and BM recipients.

Amandeep Godara, MD, of Tufts Medical Center in Boston, Massachusetts, presented these results at the 2018 BMT Tandem Meetings (abstract 30*).

“Infections are considered more common in cord blood transplant recipients based on some prior retrospective analyses,” Dr Godara noted. “But there is limited data comparing these infectious complications between cord blood transplant and peripheral blood/bone marrow stem cell transplants during the inpatient stay for the stem cell transplant.”

With this in mind, Dr Godara and his colleagues analyzed data from the Healthcare Cost and Utilization Project National Inpatient Sample. This database covers 46 US states and contains data from more than 7 million hospital stays each year.

The investigators searched the database for hospital admissions for HSCT from 2002 to 2014. They identified 2979 CB transplants and 56,845 PB or BM transplants.

The CB recipients had a median age of 48, and 55% were male. Fifty-nine percent were white, 18% Hispanic, 13% black, 5% Asian, and 5% “other.” Sixty-six percent of patients had acute leukemia, 18% non-Hodgkin lymphoma, 5% Hodgkin lymphoma, and 11% “other” diseases.

The PB/BM recipients had a median age of 45, and 58% were male. Seventy-nine percent were white, 8% Hispanic, 6% black, 3% Asian, and 4% “other.” Sixty-one percent of patients had acute leukemia, 16% non-Hodgkin lymphoma, 4% Hodgkin lymphoma, and 19% “other” diseases.

Results

Dr Godara and his colleagues compared the rates and types of infection from the time of HSCT to hospital discharge in CB and PB/BM recipients. The team also compared early inpatient mortality, the cost of hospitalization, and the length of hospital stay.

“[W]e observed a higher risk for infections in cord blood transplant patients compared to peripheral blood and bone marrow stem cell transplant patients, and this risk for infection extended through a wide spectrum of pathogens,” Dr Godara said.

“We also observed a higher all-cause inpatient mortality in cord blood transplant compared to peripheral blood and bone marrow transplant, especially in patients who had bacterial sepsis or invasive fungal infection.”

The rate of bacterial sepsis was 34.87% in CB recipients and 20.20% in PB/BM recipients (P<0.0001). Rates of viral infection were 20.05% and 8.19%, respectively (P<0.0001). And rates of invasive fungal infection were 12.87% and 7.89% (P<0.0001).

There was a similar distribution of bacterial infections in CB and PB/BM recipients. The most common was pneumonia (47% and 41%, respectively), followed by abdominal infections (29% and 31%, respectively), urinary tract infections (17% and 21%, respectively), central line-associated bloodstream infections (4% and 6%, respectively), and acute sinusitis (3% and 1%, respectively).

The rate of Clostridium difficile infection was significantly higher in CB recipients than PB/BM recipients—11.75% and 8.90%, respectively (P=0.02). However, there was no significant difference in mortality related to C. difficile—14% and 10%, respectively (P=0.3).

On the other hand, all-cause inpatient mortality was significantly higher in CB recipients than PB/BM recipients—16% and 7%, respectively (P<0.0001).

Inpatient mortality rates were significantly higher for CB recipients with bacterial sepsis (33% vs 23%, P=0.001) and invasive fungal infections (29% vs 16%, P=0.0045) but not viral infections (19% vs 17%, P=0.5).

The median length of hospital stay was 36 days for CB recipients and 25 days for PB/BM recipients. The mean inpatient charges were $448,892 and $250,437 respectively.

*Data in the abstract differ from the presentation.

Amandeep Godara, MD

SALT LAKE CITY—Results of a large, retrospective analysis support the notion that patients who receive cord blood (CB) transplants have a higher risk of infection than other hematopoietic stem cell transplant (HSCT) recipients.

Investigators found that CB recipients had a significantly higher risk of bacterial, viral, and fungal infections in the early post-transplant period than patients who received peripheral blood (PB) or bone marrow (BM) transplants.

In addition, CB recipients had longer hospital stays, higher inpatient costs, and greater inpatient mortality than PB and BM recipients.

Amandeep Godara, MD, of Tufts Medical Center in Boston, Massachusetts, presented these results at the 2018 BMT Tandem Meetings (abstract 30*).

“Infections are considered more common in cord blood transplant recipients based on some prior retrospective analyses,” Dr Godara noted. “But there is limited data comparing these infectious complications between cord blood transplant and peripheral blood/bone marrow stem cell transplants during the inpatient stay for the stem cell transplant.”

With this in mind, Dr Godara and his colleagues analyzed data from the Healthcare Cost and Utilization Project National Inpatient Sample. This database covers 46 US states and contains data from more than 7 million hospital stays each year.

The investigators searched the database for hospital admissions for HSCT from 2002 to 2014. They identified 2979 CB transplants and 56,845 PB or BM transplants.

The CB recipients had a median age of 48, and 55% were male. Fifty-nine percent were white, 18% Hispanic, 13% black, 5% Asian, and 5% “other.” Sixty-six percent of patients had acute leukemia, 18% non-Hodgkin lymphoma, 5% Hodgkin lymphoma, and 11% “other” diseases.

The PB/BM recipients had a median age of 45, and 58% were male. Seventy-nine percent were white, 8% Hispanic, 6% black, 3% Asian, and 4% “other.” Sixty-one percent of patients had acute leukemia, 16% non-Hodgkin lymphoma, 4% Hodgkin lymphoma, and 19% “other” diseases.

Results

Dr Godara and his colleagues compared the rates and types of infection from the time of HSCT to hospital discharge in CB and PB/BM recipients. The team also compared early inpatient mortality, the cost of hospitalization, and the length of hospital stay.

“[W]e observed a higher risk for infections in cord blood transplant patients compared to peripheral blood and bone marrow stem cell transplant patients, and this risk for infection extended through a wide spectrum of pathogens,” Dr Godara said.

“We also observed a higher all-cause inpatient mortality in cord blood transplant compared to peripheral blood and bone marrow transplant, especially in patients who had bacterial sepsis or invasive fungal infection.”

The rate of bacterial sepsis was 34.87% in CB recipients and 20.20% in PB/BM recipients (P<0.0001). Rates of viral infection were 20.05% and 8.19%, respectively (P<0.0001). And rates of invasive fungal infection were 12.87% and 7.89% (P<0.0001).

There was a similar distribution of bacterial infections in CB and PB/BM recipients. The most common was pneumonia (47% and 41%, respectively), followed by abdominal infections (29% and 31%, respectively), urinary tract infections (17% and 21%, respectively), central line-associated bloodstream infections (4% and 6%, respectively), and acute sinusitis (3% and 1%, respectively).

The rate of Clostridium difficile infection was significantly higher in CB recipients than PB/BM recipients—11.75% and 8.90%, respectively (P=0.02). However, there was no significant difference in mortality related to C. difficile—14% and 10%, respectively (P=0.3).

On the other hand, all-cause inpatient mortality was significantly higher in CB recipients than PB/BM recipients—16% and 7%, respectively (P<0.0001).

Inpatient mortality rates were significantly higher for CB recipients with bacterial sepsis (33% vs 23%, P=0.001) and invasive fungal infections (29% vs 16%, P=0.0045) but not viral infections (19% vs 17%, P=0.5).

The median length of hospital stay was 36 days for CB recipients and 25 days for PB/BM recipients. The mean inpatient charges were $448,892 and $250,437 respectively.

*Data in the abstract differ from the presentation.

Amandeep Godara, MD

SALT LAKE CITY—Results of a large, retrospective analysis support the notion that patients who receive cord blood (CB) transplants have a higher risk of infection than other hematopoietic stem cell transplant (HSCT) recipients.

Investigators found that CB recipients had a significantly higher risk of bacterial, viral, and fungal infections in the early post-transplant period than patients who received peripheral blood (PB) or bone marrow (BM) transplants.

In addition, CB recipients had longer hospital stays, higher inpatient costs, and greater inpatient mortality than PB and BM recipients.

Amandeep Godara, MD, of Tufts Medical Center in Boston, Massachusetts, presented these results at the 2018 BMT Tandem Meetings (abstract 30*).

“Infections are considered more common in cord blood transplant recipients based on some prior retrospective analyses,” Dr Godara noted. “But there is limited data comparing these infectious complications between cord blood transplant and peripheral blood/bone marrow stem cell transplants during the inpatient stay for the stem cell transplant.”

With this in mind, Dr Godara and his colleagues analyzed data from the Healthcare Cost and Utilization Project National Inpatient Sample. This database covers 46 US states and contains data from more than 7 million hospital stays each year.

The investigators searched the database for hospital admissions for HSCT from 2002 to 2014. They identified 2979 CB transplants and 56,845 PB or BM transplants.

The CB recipients had a median age of 48, and 55% were male. Fifty-nine percent were white, 18% Hispanic, 13% black, 5% Asian, and 5% “other.” Sixty-six percent of patients had acute leukemia, 18% non-Hodgkin lymphoma, 5% Hodgkin lymphoma, and 11% “other” diseases.

The PB/BM recipients had a median age of 45, and 58% were male. Seventy-nine percent were white, 8% Hispanic, 6% black, 3% Asian, and 4% “other.” Sixty-one percent of patients had acute leukemia, 16% non-Hodgkin lymphoma, 4% Hodgkin lymphoma, and 19% “other” diseases.

Results

Dr Godara and his colleagues compared the rates and types of infection from the time of HSCT to hospital discharge in CB and PB/BM recipients. The team also compared early inpatient mortality, the cost of hospitalization, and the length of hospital stay.

“[W]e observed a higher risk for infections in cord blood transplant patients compared to peripheral blood and bone marrow stem cell transplant patients, and this risk for infection extended through a wide spectrum of pathogens,” Dr Godara said.

“We also observed a higher all-cause inpatient mortality in cord blood transplant compared to peripheral blood and bone marrow transplant, especially in patients who had bacterial sepsis or invasive fungal infection.”

The rate of bacterial sepsis was 34.87% in CB recipients and 20.20% in PB/BM recipients (P<0.0001). Rates of viral infection were 20.05% and 8.19%, respectively (P<0.0001). And rates of invasive fungal infection were 12.87% and 7.89% (P<0.0001).

There was a similar distribution of bacterial infections in CB and PB/BM recipients. The most common was pneumonia (47% and 41%, respectively), followed by abdominal infections (29% and 31%, respectively), urinary tract infections (17% and 21%, respectively), central line-associated bloodstream infections (4% and 6%, respectively), and acute sinusitis (3% and 1%, respectively).

The rate of Clostridium difficile infection was significantly higher in CB recipients than PB/BM recipients—11.75% and 8.90%, respectively (P=0.02). However, there was no significant difference in mortality related to C. difficile—14% and 10%, respectively (P=0.3).

On the other hand, all-cause inpatient mortality was significantly higher in CB recipients than PB/BM recipients—16% and 7%, respectively (P<0.0001).

Inpatient mortality rates were significantly higher for CB recipients with bacterial sepsis (33% vs 23%, P=0.001) and invasive fungal infections (29% vs 16%, P=0.0045) but not viral infections (19% vs 17%, P=0.5).

The median length of hospital stay was 36 days for CB recipients and 25 days for PB/BM recipients. The mean inpatient charges were $448,892 and $250,437 respectively.

*Data in the abstract differ from the presentation.

AML cells

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for gemtuzumab ozogamicin (GO, Mylotarg™).

The recommendation is for GO to be used in combination with daunorubicin and cytarabine to treat patients age 15 years and older with previously untreated, de novo, CD33-positive acute myeloid leukemia (AML) but not acute promyelocytic leukemia.

The CHMP’s opinion on GO will be reviewed by the European Commission (EC).

If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

Previous rejection

The CHMP previously issued a negative opinion of GO (first in 2007, confirmed in 2008), saying the drug should not receive marketing authorization.

The proposed indication for GO at that time was as re-induction treatment in adults with CD33-positive AML in first relapse who were not candidates for other intensive re-induction chemotherapy regimens and were either older than 60 or had a duration of first remission lasting less than 12 months.

The CHMP said there was insufficient evidence to establish the effectiveness of GO in AML, and the drug’s benefits did not outweigh its risks.

Phase 3 trial

The current marketing authorization application for GO is supported by data from an investigator-led, phase 3, randomized trial known as ALFA-0701. Updated results from this trial are available in the US prescribing information for GO.

Patients and treatment

ALFA-0701 included 271 patients with newly diagnosed, de novo AML who were 50 to 70 years of age.

Patients were randomized (1:1) to receive induction consisting of daunorubicin (60 mg/m² on days 1 to 3) and cytarabine (200 mg/m² on days 1 to 7) with (n=135) or without (n=136) GO at 3 mg/m² (up to maximum of 1 vial) on days 1, 4, and 7. Patients who did not achieve a response after first induction could receive a second induction with daunorubicin and cytarabine alone.

Patients with a response received consolidation therapy with 2 courses of treatment including daunorubicin (60 mg/m² on day 1 of first consolidation course; 60 mg/m² on days 1 and 2 of second consolidation course) and cytarabine (1 g/m² every 12 hours on days 1 to 4) with or without GO at 3 mg/m² (up to a maximum of 1 vial) on day 1 according to their initial randomization.

Patients who achieved remission were also eligible for allogeneic transplant. An interval of at least 2 months between the last dose of GO and transplant was recommended.

Baseline characteristics were largely well balanced between the treatment arms, but there was a higher percentage of males in the GO arm than the control arm—55% and 44%, respectively.

Results

The study’s primary endpoint was event-free survival. The median event-free survival was 17.3 months in the GO arm and 9.5 months in the control arm (hazard ratio=0.56; 95% CI: 0.42-0.76; P<0.001).

There was no significant difference in overall survival between the treatment arms. (Updated overall survival data have not been provided).

All patients in this trial developed severe neutropenia, thrombocytopenia, and anemia. However, the incidence of prolonged, grade 3–4 thrombocytopenia in the absence of active leukemia was higher in the GO arm.

Treatment-emergent adverse events (AEs) considered most important for understanding the safety profile of GO were hemorrhage, veno-occlusive liver disease (VOD), and severe infections.

Treatment discontinuation due to any AE occurred in 31% of patients in the GO arm and 7% of those in the control arm. The most frequent AEs leading to discontinuation for patients on GO were thrombocytopenia (15%), VOD (3%), and septic shock (2%).

Fatal AEs occurred in 8 patients (6%) in the GO arm and 3 (2%) in the control arm. In the GO arm, 3 patients died of VOD, 4 died of hemorrhage-related events, and 1 died of a suspected cardiac cause. All 3 fatal AEs in the control arm were sepsis.

AML cells

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for gemtuzumab ozogamicin (GO, Mylotarg™).

The recommendation is for GO to be used in combination with daunorubicin and cytarabine to treat patients age 15 years and older with previously untreated, de novo, CD33-positive acute myeloid leukemia (AML) but not acute promyelocytic leukemia.

The CHMP’s opinion on GO will be reviewed by the European Commission (EC).

If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

Previous rejection

The CHMP previously issued a negative opinion of GO (first in 2007, confirmed in 2008), saying the drug should not receive marketing authorization.

The proposed indication for GO at that time was as re-induction treatment in adults with CD33-positive AML in first relapse who were not candidates for other intensive re-induction chemotherapy regimens and were either older than 60 or had a duration of first remission lasting less than 12 months.

The CHMP said there was insufficient evidence to establish the effectiveness of GO in AML, and the drug’s benefits did not outweigh its risks.

Phase 3 trial

The current marketing authorization application for GO is supported by data from an investigator-led, phase 3, randomized trial known as ALFA-0701. Updated results from this trial are available in the US prescribing information for GO.

Patients and treatment

ALFA-0701 included 271 patients with newly diagnosed, de novo AML who were 50 to 70 years of age.

Patients were randomized (1:1) to receive induction consisting of daunorubicin (60 mg/m² on days 1 to 3) and cytarabine (200 mg/m² on days 1 to 7) with (n=135) or without (n=136) GO at 3 mg/m² (up to maximum of 1 vial) on days 1, 4, and 7. Patients who did not achieve a response after first induction could receive a second induction with daunorubicin and cytarabine alone.

Patients with a response received consolidation therapy with 2 courses of treatment including daunorubicin (60 mg/m² on day 1 of first consolidation course; 60 mg/m² on days 1 and 2 of second consolidation course) and cytarabine (1 g/m² every 12 hours on days 1 to 4) with or without GO at 3 mg/m² (up to a maximum of 1 vial) on day 1 according to their initial randomization.

Patients who achieved remission were also eligible for allogeneic transplant. An interval of at least 2 months between the last dose of GO and transplant was recommended.

Baseline characteristics were largely well balanced between the treatment arms, but there was a higher percentage of males in the GO arm than the control arm—55% and 44%, respectively.

Results

The study’s primary endpoint was event-free survival. The median event-free survival was 17.3 months in the GO arm and 9.5 months in the control arm (hazard ratio=0.56; 95% CI: 0.42-0.76; P<0.001).

There was no significant difference in overall survival between the treatment arms. (Updated overall survival data have not been provided).

All patients in this trial developed severe neutropenia, thrombocytopenia, and anemia. However, the incidence of prolonged, grade 3–4 thrombocytopenia in the absence of active leukemia was higher in the GO arm.

Treatment-emergent adverse events (AEs) considered most important for understanding the safety profile of GO were hemorrhage, veno-occlusive liver disease (VOD), and severe infections.

Treatment discontinuation due to any AE occurred in 31% of patients in the GO arm and 7% of those in the control arm. The most frequent AEs leading to discontinuation for patients on GO were thrombocytopenia (15%), VOD (3%), and septic shock (2%).

Fatal AEs occurred in 8 patients (6%) in the GO arm and 3 (2%) in the control arm. In the GO arm, 3 patients died of VOD, 4 died of hemorrhage-related events, and 1 died of a suspected cardiac cause. All 3 fatal AEs in the control arm were sepsis.

AML cells

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for gemtuzumab ozogamicin (GO, Mylotarg™).

The recommendation is for GO to be used in combination with daunorubicin and cytarabine to treat patients age 15 years and older with previously untreated, de novo, CD33-positive acute myeloid leukemia (AML) but not acute promyelocytic leukemia.

The CHMP’s opinion on GO will be reviewed by the European Commission (EC).

If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

Previous rejection

The CHMP previously issued a negative opinion of GO (first in 2007, confirmed in 2008), saying the drug should not receive marketing authorization.

The proposed indication for GO at that time was as re-induction treatment in adults with CD33-positive AML in first relapse who were not candidates for other intensive re-induction chemotherapy regimens and were either older than 60 or had a duration of first remission lasting less than 12 months.

The CHMP said there was insufficient evidence to establish the effectiveness of GO in AML, and the drug’s benefits did not outweigh its risks.

Phase 3 trial

The current marketing authorization application for GO is supported by data from an investigator-led, phase 3, randomized trial known as ALFA-0701. Updated results from this trial are available in the US prescribing information for GO.

Patients and treatment

ALFA-0701 included 271 patients with newly diagnosed, de novo AML who were 50 to 70 years of age.

Patients were randomized (1:1) to receive induction consisting of daunorubicin (60 mg/m² on days 1 to 3) and cytarabine (200 mg/m² on days 1 to 7) with (n=135) or without (n=136) GO at 3 mg/m² (up to maximum of 1 vial) on days 1, 4, and 7. Patients who did not achieve a response after first induction could receive a second induction with daunorubicin and cytarabine alone.

Patients with a response received consolidation therapy with 2 courses of treatment including daunorubicin (60 mg/m² on day 1 of first consolidation course; 60 mg/m² on days 1 and 2 of second consolidation course) and cytarabine (1 g/m² every 12 hours on days 1 to 4) with or without GO at 3 mg/m² (up to a maximum of 1 vial) on day 1 according to their initial randomization.

Patients who achieved remission were also eligible for allogeneic transplant. An interval of at least 2 months between the last dose of GO and transplant was recommended.

Baseline characteristics were largely well balanced between the treatment arms, but there was a higher percentage of males in the GO arm than the control arm—55% and 44%, respectively.

Results

The study’s primary endpoint was event-free survival. The median event-free survival was 17.3 months in the GO arm and 9.5 months in the control arm (hazard ratio=0.56; 95% CI: 0.42-0.76; P<0.001).

There was no significant difference in overall survival between the treatment arms. (Updated overall survival data have not been provided).

All patients in this trial developed severe neutropenia, thrombocytopenia, and anemia. However, the incidence of prolonged, grade 3–4 thrombocytopenia in the absence of active leukemia was higher in the GO arm.

Treatment-emergent adverse events (AEs) considered most important for understanding the safety profile of GO were hemorrhage, veno-occlusive liver disease (VOD), and severe infections.

Treatment discontinuation due to any AE occurred in 31% of patients in the GO arm and 7% of those in the control arm. The most frequent AEs leading to discontinuation for patients on GO were thrombocytopenia (15%), VOD (3%), and septic shock (2%).

Fatal AEs occurred in 8 patients (6%) in the GO arm and 3 (2%) in the control arm. In the GO arm, 3 patients died of VOD, 4 died of hemorrhage-related events, and 1 died of a suspected cardiac cause. All 3 fatal AEs in the control arm were sepsis.

Gilead Sciences, Inc.

Gilead Sciences International Ltd. recently withdrew its application for European approval of idelalisib (Zydelig) in combination with rituximab and bendamustine for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL).

Idelalisib is currently approved in the European Union for use in combination with an anti-CD20 monoclonal antibody (rituximab or ofatumumab) to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment of CLL in the presence of 17p deletion or TP53 mutation in patients who are not eligible for any other therapies.

Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.

In seeking expanded approval for idelalisib, Gilead submitted data from a study (NCT01569295) comparing idelalisib plus bendamustine and rituximab to placebo plus bendamustine and rituximab.

Interim results from this study were published in The Lancet Oncology in March 2017.

Gilead withdrew the application for idelalisib after the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) had evaluated documentation provided by the company and formulated lists of questions.

Gilead had not responded to the last round of questions at the time of the withdrawal.

At that point, the CHMP was of the provisional opinion that idelalisib should not be approved for use in combination with rituximab and bendamustine in patients with relapsed/refractory CLL.

The CHMP said additional, longer-term data are needed to show the benefits of idelalisib plus rituximab and bendamustine outweigh the risks.

Gilead said its withdrawal of the application was based on the CHMP’s opinion that there was insufficient evidence of a favorable benefit-risk profile.

The company also said the withdrawal does not impact ongoing trials of idelalisib.

Gilead Sciences, Inc.

Gilead Sciences International Ltd. recently withdrew its application for European approval of idelalisib (Zydelig) in combination with rituximab and bendamustine for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL).

Idelalisib is currently approved in the European Union for use in combination with an anti-CD20 monoclonal antibody (rituximab or ofatumumab) to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment of CLL in the presence of 17p deletion or TP53 mutation in patients who are not eligible for any other therapies.

Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.

In seeking expanded approval for idelalisib, Gilead submitted data from a study (NCT01569295) comparing idelalisib plus bendamustine and rituximab to placebo plus bendamustine and rituximab.

Interim results from this study were published in The Lancet Oncology in March 2017.

Gilead withdrew the application for idelalisib after the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) had evaluated documentation provided by the company and formulated lists of questions.

Gilead had not responded to the last round of questions at the time of the withdrawal.

At that point, the CHMP was of the provisional opinion that idelalisib should not be approved for use in combination with rituximab and bendamustine in patients with relapsed/refractory CLL.

The CHMP said additional, longer-term data are needed to show the benefits of idelalisib plus rituximab and bendamustine outweigh the risks.

Gilead said its withdrawal of the application was based on the CHMP’s opinion that there was insufficient evidence of a favorable benefit-risk profile.

The company also said the withdrawal does not impact ongoing trials of idelalisib.

Gilead Sciences, Inc.

Gilead Sciences International Ltd. recently withdrew its application for European approval of idelalisib (Zydelig) in combination with rituximab and bendamustine for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL).

Idelalisib is currently approved in the European Union for use in combination with an anti-CD20 monoclonal antibody (rituximab or ofatumumab) to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment of CLL in the presence of 17p deletion or TP53 mutation in patients who are not eligible for any other therapies.

Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.

In seeking expanded approval for idelalisib, Gilead submitted data from a study (NCT01569295) comparing idelalisib plus bendamustine and rituximab to placebo plus bendamustine and rituximab.

Interim results from this study were published in The Lancet Oncology in March 2017.

Gilead withdrew the application for idelalisib after the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) had evaluated documentation provided by the company and formulated lists of questions.

Gilead had not responded to the last round of questions at the time of the withdrawal.

At that point, the CHMP was of the provisional opinion that idelalisib should not be approved for use in combination with rituximab and bendamustine in patients with relapsed/refractory CLL.

The CHMP said additional, longer-term data are needed to show the benefits of idelalisib plus rituximab and bendamustine outweigh the risks.

Gilead said its withdrawal of the application was based on the CHMP’s opinion that there was insufficient evidence of a favorable benefit-risk profile.

The company also said the withdrawal does not impact ongoing trials of idelalisib.

Photo from Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a label variation for Neulasta® (pegfilgrastim) to include the Neulasta® Onpro® Kit.

The Neulasta Onpro Kit is an on-body injector (OBI) delivery system for Neulasta, which is approved in the European Union to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukemia and myelodysplastic syndromes).

The Neulasta Onpro Kit includes a specifically designed Neulasta pre-filled syringe along with a single-use OBI. The small, lightweight OBI is applied to a patient’s skin on the same day of chemotherapy.

The OBI is intended to facilitate timed delivery of the correct dose of Neulasta and eliminate the need for patients to return to a healthcare setting the day after they receive chemotherapy.

The CHMP’s opinion on the Neulasta Onpro Kit will be reviewed by the European Commission (EC).

If the EC agrees with the CHMP, the centralized marketing authorization of Neulasta will be updated to include information on the Neulasta Onpro Kit in the drug’s label.

This change will be valid throughout the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions about Neulasta’s label on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

Photo from Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a label variation for Neulasta® (pegfilgrastim) to include the Neulasta® Onpro® Kit.

The Neulasta Onpro Kit is an on-body injector (OBI) delivery system for Neulasta, which is approved in the European Union to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukemia and myelodysplastic syndromes).

The Neulasta Onpro Kit includes a specifically designed Neulasta pre-filled syringe along with a single-use OBI. The small, lightweight OBI is applied to a patient’s skin on the same day of chemotherapy.

The OBI is intended to facilitate timed delivery of the correct dose of Neulasta and eliminate the need for patients to return to a healthcare setting the day after they receive chemotherapy.

The CHMP’s opinion on the Neulasta Onpro Kit will be reviewed by the European Commission (EC).

If the EC agrees with the CHMP, the centralized marketing authorization of Neulasta will be updated to include information on the Neulasta Onpro Kit in the drug’s label.

This change will be valid throughout the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions about Neulasta’s label on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

Photo from Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a label variation for Neulasta® (pegfilgrastim) to include the Neulasta® Onpro® Kit.

The Neulasta Onpro Kit is an on-body injector (OBI) delivery system for Neulasta, which is approved in the European Union to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukemia and myelodysplastic syndromes).

The Neulasta Onpro Kit includes a specifically designed Neulasta pre-filled syringe along with a single-use OBI. The small, lightweight OBI is applied to a patient’s skin on the same day of chemotherapy.

The OBI is intended to facilitate timed delivery of the correct dose of Neulasta and eliminate the need for patients to return to a healthcare setting the day after they receive chemotherapy.

The CHMP’s opinion on the Neulasta Onpro Kit will be reviewed by the European Commission (EC).

If the EC agrees with the CHMP, the centralized marketing authorization of Neulasta will be updated to include information on the Neulasta Onpro Kit in the drug’s label.

This change will be valid throughout the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions about Neulasta’s label on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.